Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Urology, Tel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.
Urol Oncol. 2021 Nov;39(11):791.e17-791.e24. doi: 10.1016/j.urolonc.2021.08.018. Epub 2021 Sep 25.
Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC.
After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size).
The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011).
In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.
在透明细胞肾细胞癌（ccRCC）中，复发性基因组改变与治疗结果相关；然而，目前的术前预测模型并不包括已知的遗传预测因子。我们旨在探讨常见体细胞突变在预测接受局部 ccRCC 治疗的患者发生转移性疾病中的价值。
在获得机构审查委员会批准后，收集了 2005 年至 2015 年间接受基因测序的 254 例局部 ccRCC 患者的数据。在肾切除术肿瘤标本中评估了 VHL、PBRM1、SETD2、BAP1 和 KDM5C 的突变状态，该标本作为活检突变状态的替代物。使用 Raj 等人的术前列线图预测 12 年无转移生存率（MFP）。本研究的结局是 MFP；通过 Cox 回归模型评估 MFP 与突变状态之间的关系，该模型调整了术前列线图变量（年龄、性别、偶然发现、淋巴结病、坏死和大小）。
该研究队列包括 188 名男性（74%）和 66 名女性（26%），中位年龄为 58 岁。254 例患者中有 152 例（60%）存在 VHL 突变，91 例（36%）存在 PBRM1 突变，32 例（13%）存在 SETD2 突变，19 例（8%）存在 BAP1 突变，19 例（8%）存在 KDM5C 突变。幸存者的中位随访时间为 8.1 年。估计 12 年 MFP 为 70%（95%CI：63%-75%）。单变量分析显示，SETD2（HR：3.30）、BAP1（HR：2.44）和 PBRM1（HR：1.78）与转移风险增加显著相关。在调整现有列线图中已知的术前预测因子后，SETD2 突变与肾切除术后转移率升高仍相关（HR：2.09，95%CI：1.19-3.67，P=0.011）。
在当前的探索性分析中，SETD2 突变是接受局部 ccRCC 治疗的患者 MFP 的显著预测因子。我们的研究结果支持未来评估术前肾活检样本中遗传改变作为治疗结果潜在预测因子的研究。
